Summary Epithelial resident T cells that express the gd T cell receptor play a crucial role in maintaining homeostasis at mucosal surfaces. This is particularly challenging in the intestine which is constantly bathed with commensal microbes as well as ingested potentially pathogenic bacteria. Disruption of this fine balance can lead to systemic infection. gd T cell receptor-expressing intraepithelial lymphocytes (gd IEL) provide important protections against systemic infection, however the molecular mechanisms driving their protective functions are not well characterized. Crosstalk between gd T cells and their neighboring epithelial cells is vital to this process and clues from the regulation of gd T cells in the epidermis have implicated CD100 and JAML as important players. We propose that CD100 and JAML are crucial regulators of the gd IEL response to intestinal infection and provide protections against bacterial translocation across the epithelium and limit subsequent systemic infection. We will test this hypothesis through analysis of gd IEL responses to Salmonella typhimurium infection in the presence or absence of CD100 and JAML. We will use congenic animals to add back CD100- or JAML-sufficient gd IEL to demonstrate the specific requirement for these molecules on gd IEL in pathogen responses. Information gained through these studies may demonstrate the potential for these molecules as new targets for therapeutic strategies. Additionally the data obtained will provide insight into the mechanisms of gd T cell responses to infection in other mucosal sites and will thus contribute to our understanding of the molecular mechanisms governing mucosal immunity.